ATM activation in hypoxia - causes and consequences

The DNA damage response is a complex signaling cascade that is triggered by cellular stress. This response is essential for the maintenance of genomic integrity and is considered to act as a barrier to the early stages of tumorigenesis. The integral role of ataxia telangiectasia mutated (ATM) kinase in the response to DNA damaging agents is well characterized; however, ATM can also be activated by non-DNA damaging agents. In fact, much has been learnt recently about the mechanism of ATM activation in response to physiologic stresses such as hypoxia that do not induce DNA damage. Regions of low oxygen concentrations that occur in solid tumors are associated with a poor prognostic outcome irrespective of treatment modality. Severe levels of hypoxia induce replication stress and trigger the activation of DNA damage response pathways including ataxia telangiectasia and Rad3-related (ATR)- and ATM-mediated signaling. In this review, we discuss hypoxia-driven ATM signaling and the possible contribution of ATM activation in this context to tumorigenesis.